Acute Pyelonephritis in Pregnancy

1. What every clinician should know

Clinical features and incidence

Acute pyelonephritis in pregnancy complicates up to 2% of all pregnancies and has been associated with significant maternal and fetal morbidity and mortality. Pre-term delivery, maternal sepsis, renal failure and respiratory distress are among the complications associated with acute pyelonephritis and maternal-fetal compromise.

Acute pyelonephritis is one of the most common indications for antepartum hospitalization, estimated at approximately 9.7% of all indications for predelivery hospitalization, and when diagnosed, conventional treatment includes intravenous fluid and parenteral antibacterial administration, and careful monitoring of fluid balance. There is some evidence to support the ambulatory treatment of pregnant women with pyelonephritis who do not demonstrate signs of overt sepsis and preterm contractions in the first and early second trimesters, but the majority of women with acute pyelonephritis in pregnancy are traditionally managed as inpatients.

With higher frequencies of the associated complications of pyelonephritis in pregnancy, such as preterm labor and delivery and acute respiratory compromise, occurring in the third trimester compared to earlier gestational ages, inpatient management is considered the standard of care in the third trimester.

Risk factors

Physiologic and anatomic changes that occur as a result of the gravid state predispose women to UTI in general. Progesterone induces relaxation of the smooth muscles of renal calyces and ureters, causing dilatation and stasis. Additionally, the growing uterus causes a mechanical compression on the ureters, particularly on the right. In addition, mechanical compression of the bladder and relaxation in detrusor muscle tone, lending to post-void residual urine volume, contribute to higher propensities toward UTI in pregnancy. Glucosuria and alkalinization of the urine also exacerbates the risk for UTI. The physiologic and anatomic changes of pregnancy from the effects of progesterone facilitate bacterial growth.

Asymptomatic bacteriuria is reported to complicate between 2% and 10% of pregnancies. It is one of the strongest predictors for development of acute pyelonephritis in pregnancy, increasing the risk for this complication 20-30 fold. For this reason, asymptomatic bacteriuria has historically been treated. More contemporary research, however, has questioned this paradigm. A large randomized controlled trial which screened more than 4,200 women in the Netherlands for asymptomatic bacteriuria found a low overall incidence of pyelonephritis when left untreated (2.4% vs. 0.6%). While women untreated for asymptomatic bacteriuria were four times more likely to develop pyelonephritis during pregnancy, the authors point out that the low overall incidence of this complication calls into question the routine screen-treat policy for asymptomatic bacteriuria in pregnancy.

Moreover, women with anatomical defects in the urinary tract, such as incompetent vesicourethral valves, may develop reflux of urine, which predisposes to UTI. The presence of renal calculi provides a good environment for bacterial growth as well. Medical conditions such as diabetes mellitus, neurogenic bladder (e.g. from spinal cord injury), sickle cell disease and trait, are all risk factors for developing UTI.

Although less common, maternal history of renal disease should be considered as a predisposing feature of acute pyelonephritis. Maternal diagnosis of systemic lupus erythematosus, chronic glomerulonephritis, adult polycystic kidney disease, chronic pyelonephritis and renal transplantation status have all been associated with acute pyelonephritis in pregnancy.

Other risk factors elucidated from a retrospective review of 242 non-pregnant women of aged 18-49 years with pyelonephritis are frequency of sexual intercourse in the previous 30 days, recent spermicide use, recent UTI and recent incontinence. Interestingly, women of lower socio-economic status are at increased risk for UTI and acute pyelonephritis. Most of the evidence about UTI supports an ascending mode of infection from lower UTI to pyelonephritis.

2. Diagnosis and differential diagnosis

Establishing the diagnosis

Clinical signs and symptoms of acute pyelonephritis includes the typical presentation of UTI, to include dysuria, frequency, urgency, hematuria and suprapubic pain. In addition, classic upper urinary tract symptoms to include flank or back pain may be accompanied by systemic symptoms (e.g. fever, chills, abdominal pain, nausea and vomiting). Clinical signs of fever, costovertebral angle tenderness (CVAT) with or without leukocytosis are typically present. However, a potential confounder in the diagnosis is that it can present with nonspecific symptoms. Therefore, the clinical index for suspicion of UTI in pregnant patients should be high.

Diagnostic criteria and tests

Urinalysis and urine culture are the initial tests to perform in women who present with clinical signs and symptoms of UTI, (with the most severe form of UTI being acute pyelonephritis). Urinary dipstick testing for the presence of leukocyte esterase and nitrites is often positive, with sensitivity and specificity for the combination of 92% and 95%, respectively. The diagnosis is confirmed by the final urine cultures, obtained usually by midstream clean-catch but occasionally by urethral catheterization, and less commonly by suprapubic aspiration

According to the Infectious Diseases Society of America (IDSA) consensus definition of pyelonephritis, colony counts greater than or equal to 100,000 cfu/ml from clean-catch voided specimens are acceptable for use in antimicrobial treatment studies, and provide a sensitivity of 90-95%. One or two bacteria per high-power field on a catheterized urine specimen, or more than 20 bacteria per high-power field on spun urine, closely correlates with greater than 100,000 cfu/ml bacteria on urine culture. Pyuria or the presence of leukocyte casts are also consistent with the diagnosis. The ISDA has also defined asymptomatic bacteriuria as greater than 100,000 cfu/mL, and left untreated, can lead to up to 40% of cases of pyelonephritis.

In addition to urinalysis and urine culture, laboratory evaluation should include a complete blood cell count with differential to evaluate for leukocytosis and anemia, and serum chemistry evaluation. Electrolyte abnormalities are also common and should be corrected. Monitoring serum lactate dehydrogenase levels is a common practice and is used to evaluate for hemolysis attributed to endotoxin mediated hemolysis. Transient renal insufficiency has been noted.

Previous estimates were that a quarter of women with acute pyelonephritis in pregnancy developed renal insufficiency, but more recent studies suggest that the rate may be lower (2%), possibly due to earlier presentation for treatment and intravenous fluid hydration. Spontaneous resolution of the abnormal renal function should be expected as the acute infection clears, although there is some evidence that a minority of women will have permanent renal impairment following a bout of pyelonephritis in pregnancy.

In addition, blood cultures are often obtained when a patient presents with signs and symptoms of acute pyelonephritis. However, there is evidence to challenge this practice, as most microbes isolated from blood cultures are the same as those isolated from urine cultures.

In a retrospective study of 391 patients with pyelonephritis in pregnancy, only 6% of patients required changes in antibiotic therapy, most commonly for persistent pyrexia and not correlated with urine or blood culture results. A change in management because of bacteremia alone occurred in only 1% of cases. The limited utility of routine cultures in the clinical management of patients suggested that patient care would not be compromised in their absence. A recent meta-analysis found no high-quality randomized controlled trials assessing the benefit for or against the use of routine blood cultures in the management of acute pyelonephritis in pregnancy. Until such time that well-designed randomized controlled trials exist, there is evidence to obtain blood cultures only if the patient is febrile greater than 39°C, appears to have sepsis or has a major co-morbidity such as diabetes mellitus or respiratory distress syndrome.

Other possible diagnoses

Acute pyelonephritis in pregnancy is a diagnosis made without the support of imaging. However, if the patient continues to mount fevers more than 72 hours after inpatient admission and appropriate parenteral antibiotics are initiated, a renal ultrasound should be obtained to evaluate for nephrolithiasis or renal abscess. Intravenous pyelography is also a radiologic modality that has been historically used to aid in the diagnosis of urinary tract anatomic or functional deficits; computed tomography of the urinary tract with minimal number of exposures obtained so as to minimize fetal exposure to ionizing radiation has replaced IVP. Less commonly practiced, magnetic resonance imaging may be obtained to evaluate for urinary tract obstruction.

3. Management

The standard approach to the treatment of acute pyelonephritis in pregnancy is hospitalization, and administration of intravenous hydration, antipyretics and parenteral antimicrobial therapy. There is insufficient data to recommend one antibacterial regimen at the current time, although consideration should be given to the antimicrobial-resistance patterns at a given hospital.

As more microorganisms become resistant to antimicrobial therapies, clinicians will face additional treatment challenges. There issome evidence to support the ambulatory treatment of pregnant women at less than 24 weeks gestational age with acute pyelonephritis provided these women are relatively healthy and do not manifest signs or symptoms of respiratory insufficiency or sepsis. However, the clinician must be cautioned about the growing resistance to common oral antibiotic regimens.

In 2005, the North American Urinary Tract Infection Collaborative Alliance (NAUTICA) reported on the susceptibility of outpatient uropathogen isolates to antibiotics commonly used to treat urinary tract infection. One thousand nine hundred and ninety urinary isolates were obtained from 41 centers in the U.S. and Canada. E. coli represented 57.5% of all outpatient urinary isolates, with Klebsiella pneumoniae (12.4%), Enterococcus spp. (6.6%) and Proteus mirabilis (5.4%) making up the remaining majority.

Among all the isolates, 45.9% were resistant to ampicillin, 20.4% to SMX/TMP, 14.3% to nitrofurantoin, 9.7% to ciprofloxacin and 8.1% to levofloxacin. Similar findings were demonstrated in a recent, large single-center study performed in Australia which evaluated the urinary isolates of 230 cases of pyelonephritis and more than 30,000 uncomplicated UTI's. More than 90% of cases of pyelonephritis and 66% of UTI's were attributed to E. coli. Klebsiella, Enterococcus, and Proteus spp. represented the majority of other isolates. Approximately 50% of all urinary isolates were resistant to ampicillin, and 30% resistant to SMX/TMP. Ambulatory treatment of acute pyelonephritis in pregnancy beyond 24 weeks appears to be limited in its applicability and is therefore not recommended.

Antimicrobials should be initiated immediately after urinalysis and urine cultures are taken. Amino- and carboxy-penicillin derivatives, ureidopenicillins and cephalosporins have good safety profiles in pregnancy (most are U.S. Food and Drug Administration Category B) and have good urinary penetration. Ampicillin had historically been the drug of choice for acute pyelonephritis in pregnancy because of minimal maternal-fetal risk, low-cost, and good urinary concentrations, but more recently has had a high frequency of resistance, especially in certain E. coli strains. Cefazolin has now replaced ampicillin as the initial broad-spectrum antibiotic of choice, and has the added benefit of being cost-effective.

Gentamicin (an aminoglycoside) has the ability to be reabsorbed into renal tissue and also has the desired effect of binding in the proximal collecting tubule epithelium. However, the administration of this drug should be carefully weighed against the risk for ototoxicity, as well as the fact that it is a Category C drug and has potential for teratogenic effects, although no true cases of deafness have been identified following gentamicin exposure.

Additionally, there is evidence that any toxicity associated with gentamicin use is dose-dependent. Therefore, given that gentamicin has a narrow therapeutic index that needs to be monitored, regular maternal-serum levels of gentamicin need to be obtained to ensure therapeutic levels. Gentamicin must be renally dosed for any patient with renal insufficiency.

There are a number of anti-microbial drugs to avoid during pregnancy despite their utility in non-pregnant populations to tret UTI. The class of antibiotics known as tetracyclines are contraindicated in pregnancy due to their calcium chelating properties, resulting in fetal tooth discoloration and inhibition of bone growth. Fluoroquinolones have excellent urinary penetration but are also contraindicated in pregnancy due to the risk of fetal arthropathy.

Intravenous antimicrobial therapy is recommended to be continued for an average of 48 hours and then transitioned to oral antibiotics, with the oral therapy duration target of 10-14 days.

The initiation of empiric parenteral antibiotics should yield clinical improvement in symptoms, and febrile episodes should subside over a few days. Temperature fluctuations can be quite marked in the initial phase of treatment, with ranges of temperatures encompassing hypothermia to fever. However, if either criterion is not met, additional evaluation is merited. The urine cultures obtained prior to initiating antibiotic therapy should be evaluated for adequacy of anti-microbial coverage, and appropriate changes made in choice of antibiotics if necessary.

Additionally, the patient should be evaluated for other sources of infection, anatomic abnormalities in the urinary tract, including nephrolithiasis, and underlying disease processes that might preclude appropriate response to therapy.

Close surveillance of the maternal respiratory status during treatment for acute pyelonephritis is imperative. Careful administration of intravenous fluids should occur with watchful observation of fluid balance to avoid fluid overload. Pulmonary edema associated with acute pyelonephritis in pregnancy will manifest with symptoms of shortness of breath, tachypnea and low oxygen saturation.

Similarly, close observation of the other maternal vital signs is necessary to evaluate for the presence of systemic inflammatory syndrome or sepsis. Hypotension, tachycardia and low urine output may be seen in association with acute pyelonephritis in pregnancy. Appropriate treatment for this is largely supportive, and may include pressor support. Invasive cardiac monitoring is rarely needed for this infectious complication of pregnancy.

If respiratory compromise is suspected, an evaluation of fluid balance isimportant, coupled with oximetry, arterial blood gas assessment and chest roentgenography. Respiratory insufficiency is a potentially life-threatening complication of acute pyelonephritis in pregnancy and is rarely seen in association with acute pyelonephritis in non-pregnant individuals.

If renal insufficiency is suspected, close observation with 24-hour urine protein/creatinine or spot urine protein/creatinine ratios may be followed sequentially throughout gestation and following delivery.

4. Complications

There are both maternal and fetal complications of acute pyelonephritis in pregnancy.

Anemia is the most common complication encountered in association with the disease, occurring in approximately 25% of patients. Usually blood transfusions are not necessary and careful monitoring of the hemoglobin and hematocrit is adequate. The etiology of this is hemolysis due to endotoxemia.

The incidence of bacteremia is approximately 15-20% of women with pyelonephritis. Urosepsis is a potentially fatal complication that results from bacteremia. The pathogenesis of urosepsis is mediated by endotoxin present in the cell wall of Gram negative bacteria. These endotoxins lead to a cascade response of cytokines, histamine and bradykinins. These inflammatory molecules cause capillary endothelial damage, vasodilation resulting in decreased systemic vascular resistance and a state of high cardiac output.

A serious complication of urosepsis is septic shock and disseminated intravascular coagulation (DIC), and these patients require close monitoring in an intensive care unit, often with pulmonary artery catheterization. The mainstay of treatment is fluid resuscitation while scrutinizing the adequacy of antimicrobial coverage. Pressors such as dopamine may be required to maintain systolic perfusion to end organs and adequate urine output. In the case of DIC, appropriate transfusions with blood products and monitoring of coagulopathies should be instituted without delay.

Another potentially fatal complication of the disease is respiratory insufficiency. The incidence of respiratory insufficiency is reported at 2-8% of all pregnant patients with acute pyelonephritis. The clinical presentation includes dyspnea, tachypnea and hypoxia. On imaging, chest plain films will reveal pulmonary edema. This condition can be managed with supplemental oxygen therapy, careful fluid balance and diuresis. However, it can easily progress to the need for mechanical ventilation.

In one retrospective investigation, ARDS was diagnosed more frequently in women who had been treated with b-sympathomimetic tocolytic therapy and had received excessive intravenous hydration. This is a particularly challenging aspect because one of the complications of acute pyelonephritis in pregnancy, pre-term labor, is treated by tocolytics, which will lend itself to another complication of respiratory distress.

Recurrent pyelonephritis occurs in approximately 8-20% of women before delivery. The possibility of permanent renal damage must be considered when discussing recurrent infection. The frequency of recurrences may be reduced with careful post treatment surveillance for recurrent infection and the use of suppressive therapy. The risk of preterm labor and delivery attributable to pyelonephritis in pregnancy is difficult to ascertain, particularly because delivery may not occur during the admission for the acute disease, and the risk factors for both pyelonephritis and preterm delivery overlap.

Of 368 women delivered at Parkland Hospital with a history of pyelonephritis during the pregnancy, 19/368 (5%) delivered at less than 37 weeks, and only 4/368 (1%) delivered preterm during their admission for acute pyelonephritis. Although most will not deliver, the majority of women with pyelonephritis in the second and third trimesters will experience uterine contractions; therefore, the threat of preterm delivery is taken seriously. Another recently published study attributed a higher percentage of preterm labor to pyelonephritis as compared to the Parkland Hospital study. This can be explained by the difficulty in evaluating each outcome separately because the risk factors for preterm labor often coincide with the risk factors for acute pyelonephritis. More research should be done to elucidate each risk factor for preterm labor independently.

Despite the presence of uterine contractions, there is often little or no cervical change. It has been suggested that the use of tocolytic therapy be reserved for those patients who do exhibit cervical change, as tocolysis may aggravate the response to endotoxemia and predispose pregnant women to pulmonary edema and respiratory insufficiency.

5. Prognosis and outcome

When acute pyelonephritis during pregnancy is diagnosed and treated in a timely manner, the majority of maternal-fetal outcomes are favorable. If after initiation of IV fluid hydration, parenteral antibiotics and monitoring fluid status, the patient is afebrile for more than 48 hours and has symptomatic improvement, she is discharged home with outpatient completion of oral antibiotics for a total of 2 weeks. Upon completion of the antibiotic regimen, a urine culture needs to be sent as a test of cure.

Historical data has shown that acute pyelonephritis complicates up to 2% of pregnancies. More recent data from Kaiser Permanente Southern California hospitals suggest that the frequency of pyelonephritis diagnoses is lower in this integrated health care system and found rates as low as 0.5%, which is considerably less than the National Hospital Discharge Survey's frequency of 12.8%. This may be due in part to socioeconomic features of the pregnant women who received prenatal care in this system, improved surveillance and clinical vigilance for pyelonephritis.

Additionally, the patient should continue antibiotic prophylaxis for the remainder of the pregnancy, and monthly urine cultures should be obtained to monitor recurrence of acute pyelonephritis. Again, the recurrence rate is approximately 8-20%. There is the potential for long-term renal insufficiency after a single bout of acute pyelonephritis in pregnancy, but the potential is low.

Maternal-fetal morbidity does not differ significantly between first and second/third trimesters, and first trimester acute pyelonephritis should be treated early and aggressively to prevent maternal-fetal compromise.

6. What is the evidence for specific management and treatment recommendations

(This report characterizes of frequencies with which associated morbidities of acute pyelonephritis in pregnancy are encountered. Clearly, there are more morbidities associated with advancing gestational age.)

(This report outlines the etiology of anemia associated with acute pyelonephritis in pregnancy. Approximately 25% of cases of acute pyelonephritis in pregnancy will be complicated by this hematologic abnormality.)

(This is a description of the frequency of acute pyelonephritis in pregnancy and its associated complications from a large inner-city facility in Dallas, Texas. It provides a contemporary look at this commonly encountered complication of pregnancy.)

(This important comparative investigation outlines the importance of antibiotic suppression for the duration of pregnancy following treatment for acute pyelonephritis in pregnancy, with a nearly 30% reduction in the frequency of positive urine cultures in women treated with prophylaxis versus those without.)

(This is the first of two randomized, controlled trials evaluating the utility of ambulatory treatment of acute pyelonephritis in pregnancy. The results indicate that this approach can be used in select cases where women demonstrate no outward signs of sepsis or threat of pregnancy loss, but that many women will not qualify for those reasons and others, including inability to tolerate oral intake and orally administered medications.)

(This is a report of all urinary tract infections in women and has a section focused on UTIs in pregnancy. Etiologies, risk factors, associated complications and outcomes are well-described in this report.)

(This is a seminal description evaluating risk factors for the development of pulmonary injury associated with acute pyelonephritis in pregnancy. Risk factors include advanced gestational age, use of beta-mimetic tocolytic agents and the presence of Klebsiella pneumoniae as the causative organism.)

(This is the second in a series of randomized, controlled trials from the same institution evaluating the utility of ambulatory treatment of acute pyelonephritis in pregnancy after fetal viability has been achieved at 24 weeks. The vast majority of women will not qualify for this approach to treatment, and many women will demonstrate conditions which will eventually require hospitalization. This report demonstrated that the utility of outpatient treatment of acute pyelonephritis in pregnancy after 24 weeks gestational age is limited.)

(This report describes the limited clinical utility of blood and urine cultures in the treatment of acute pyelonephritis in pregnancy. Positive results from blood cultures are obtained infrequently, and when a bacterial isolate is identified from blood cultures, it rarely differs from the uropathogenic isolate.)